WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 408097
CAS#: 327031-55-0 (free base)
Description: VLX600 is a Iron Chelator that Target Both Proliferating and Quiescent Cancer Cells. VLX600 potentiated the effect of radiation in tumor spheroids in a synergistic manner. VLX600 is a lipophilic cation-based triazinoindolyl-hydrazone compound and mitochondrial oxidative phosphorylation (OxPhos) inhibitor, with potential antineoplastic activity. Upon infusion, in normal cells and proliferating tumor cells where glucose is readily available,
MedKoo Cat#: 408097
Name: VLX600
CAS#: 327031-55-0 (free base)
Chemical Formula: C17H15N7
Exact Mass: 317.1389
Molecular Weight: 317.356
Elemental Analysis: C, 64.34; H, 4.76; N, 30.90
Related CAS #: 327031-55-0 (free base) 1622945-04-3 (free base) VLX600 HCl
Synonym: VLX600; VLX-600; VLX 600;
IUPAC/Chemical Name: 2-[1-(2-[6-Methyl-5H-[1,2,4]triazino[5,6-b]indol-3-yl]hydrazin-1-ylidene)ethyl]pyridine
InChi Key: UQOSBPRTQFFUOA-SRZZPIQSSA-N
InChi Code: InChI=1S/C17H15N7/c1-10-6-5-7-12-14(10)19-16-15(12)22-24-17(20-16)23-21-11(2)13-8-3-4-9-18-13/h3-9H,1-2H3,(H2,19,20,23,24)/b21-11+
SMILES Code: C/C(C1=NC=CC=C1)=N\NC2=NN=C3C(NC4=C3C=CC=C4C)=N2
Appearance: Solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO
Shelf Life: >3 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
| Biological target: | VLX600 is an iron-chelating inhibitor of oxidative phosphorylation (OXPHOS) that causes mitochondrial dysfunction and induces a strong shift to glycolysis. |
| In vitro activity: | VLX600 was identified in a screen for compounds active on 3-D tumor spheroids but also shows antiproliferative activity on colon cancer cell lines in monolayer culture. The effect of VLX600 was examined on a number of colon cancer cell lines and generally found IC50 values in the order of 1 μM (Fig. 3A–G). VLX600 was more potent than other iron chelators (i.e. Triapine (3aminopyridine-2-carboxaldehyde-thiosemicarbazone), CPX, VLX5019, and deferoxamine) (Fig. 3A–G). DNA synthesis of colon cancer cells grown in monolayer culture was inhibited as evidenced by decreased incorporation of 5-ethynyl-2′-deoxyuridine (EdU) (Fig. 3H,I). The catalytic activity of ribonucleotide reductase is dependent on an iron-binding site in the M2 subunit of the enzyme and iron chelators have been found to inhibit this enzyme20. As expected, VLX600 inhibited ribonucleotide reductase activity in vitro (Fig. 3J). Reference: Sci Rep. 2016; 6: 38343. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5141479/ |
| In vivo activity: | To study the effects of VLX600 in vivo, the drug was injected intravenously in NMRI mice. The compound was rapidly distributed and finally eliminated with a half-life of ~4–5 h. Using the maximally tolerated dose, antitumour activity was observed in both HCT116 and HT29 colon cancer xenografts (Fig. 7b–e). Importantly, minimal systemic toxicity was observed as evidenced by no loss of body mass and no or minor changes in plasma parameters such as liver alanine aminotransferase, blood glucose and total protein (Supplementary Fig. 7a,b). Sections from VLX600-treated HCT116 tumours were examined. VLX600 treatment resulted in a decreased Ki67-labelling index (Fig. 7f) consistent with growth arrest. Large cytoplasmic vesicles were also observed (Fig. 7g), suggesting that the compound induced the formation of autolysosomes also in vivo. On the basis of the results of this study, a model for the effect of VLX600 on normal and tumour cells in different microenvironments is presented in Fig. 8. Reference: Nat Commun. 2014 Feb 18; 5: 3295. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3929804/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 19.0 | 59.87 |
The following data is based on the product molecular weight 317.356 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 1.15 mL | 5.76 mL | 11.51 mL |
| 5 mM | 0.23 mL | 1.15 mL | 2.3 mL |
| 10 mM | 0.12 mL | 0.58 mL | 1.15 mL |
| 50 mM | 0.02 mL | 0.12 mL | 0.23 mL |
| Formulation protocol: | 1. Karlsson H, Senkowski W, Fryknäs M, Mansoori S, Linder S, Gullbo J, Larsson R, Nygren P. A novel tumor spheroid model identifies selective enhancement of radiation by an inhibitor of oxidative phosphorylation. Oncotarget. 2019 Sep 3;10(51):5372-5382. doi: 10.18632/oncotarget.27166. PMID: 31523395; PMCID: PMC6731106. 2. Fryknäs M, Zhang X, Bremberg U, Senkowski W, Olofsson MH, Brandt P, Persson I, D'Arcy P, Gullbo J, Nygren P, Schughart LK, Linder S, Larsson R. Iron chelators target both proliferating and quiescent cancer cells. Sci Rep. 2016 Dec 7;6:38343. doi: 10.1038/srep38343. PMID: 27924826; PMCID: PMC5141479. 3. Zhang X, Fryknäs M, Hernlund E, Fayad W, De Milito A, Olofsson MH, Gogvadze V, Dang L, Påhlman S, Schughart LA, Rickardson L, D'Arcy P, Gullbo J, Nygren P, Larsson R, Linder S. Induction of mitochondrial dysfunction as a strategy for targeting tumour cells in metabolically compromised microenvironments. Nat Commun. 2014;5:3295. doi: 10.1038/ncomms4295. PMID: 24548894; PMCID: PMC3929804. |
| In vitro protocol: | 1. Karlsson H, Senkowski W, Fryknäs M, Mansoori S, Linder S, Gullbo J, Larsson R, Nygren P. A novel tumor spheroid model identifies selective enhancement of radiation by an inhibitor of oxidative phosphorylation. Oncotarget. 2019 Sep 3;10(51):5372-5382. doi: 10.18632/oncotarget.27166. PMID: 31523395; PMCID: PMC6731106. 2. Fryknäs M, Zhang X, Bremberg U, Senkowski W, Olofsson MH, Brandt P, Persson I, D'Arcy P, Gullbo J, Nygren P, Schughart LK, Linder S, Larsson R. Iron chelators target both proliferating and quiescent cancer cells. Sci Rep. 2016 Dec 7;6:38343. doi: 10.1038/srep38343. PMID: 27924826; PMCID: PMC5141479. |
| In vivo protocol: | 1. Karlsson H, Senkowski W, Fryknäs M, Mansoori S, Linder S, Gullbo J, Larsson R, Nygren P. A novel tumor spheroid model identifies selective enhancement of radiation by an inhibitor of oxidative phosphorylation. Oncotarget. 2019 Sep 3;10(51):5372-5382. doi: 10.18632/oncotarget.27166. PMID: 31523395; PMCID: PMC6731106. 2. Zhang X, Fryknäs M, Hernlund E, Fayad W, De Milito A, Olofsson MH, Gogvadze V, Dang L, Påhlman S, Schughart LA, Rickardson L, D'Arcy P, Gullbo J, Nygren P, Larsson R, Linder S. Induction of mitochondrial dysfunction as a strategy for targeting tumour cells in metabolically compromised microenvironments. Nat Commun. 2014;5:3295. doi: 10.1038/ncomms4295. PMID: 24548894; PMCID: PMC3929804. |
1: Kanakkanthara A, Kurmi K, Ekstrom TL, Hou X, Purfeerst ER, Heinzen EP, Correia C, Huntoon CJ, O'Brien D, Wahner Hendrickson AE, Dowdy SC, Li H, Oberg AL, Hitosugi T, Kaufmann SH, Weroha SJ, Karnitz LM. BRCA1 Deficiency Upregulates NNMT, Which Reprograms Metabolism and Sensitizes Ovarian Cancer Cells to Mitochondrial Metabolic Targeting Agents. Cancer Res. 2019 Dec 1;79(23):5920-5929. doi: 10.1158/0008-5472.CAN-19-1405. Epub 2019 Oct 16. PMID: 31619387; PMCID: PMC6891213.
2: Karlsson H, Senkowski W, Fryknäs M, Mansoori S, Linder S, Gullbo J, Larsson R, Nygren P. A novel tumor spheroid model identifies selective enhancement of radiation by an inhibitor of oxidative phosphorylation. Oncotarget. 2019 Sep 3;10(51):5372-5382. doi: 10.18632/oncotarget.27166. PMID: 31523395; PMCID: PMC6731106.
3: Mody K, Mansfield AS, Vemireddy L, Nygren P, Gulbo J, Borad M. A phase I study of the safety and tolerability of VLX600, an Iron Chelator, in patients with refractory advanced solid tumors. Invest New Drugs. 2019 Aug;37(4):684-692. doi: 10.1007/s10637-018-0703-9. Epub 2018 Nov 21. PMID: 30460505.
4: Vitiello GA, Medina BD, Zeng S, Bowler TG, Zhang JQ, Loo JK, Param NJ, Liu M, Moral AJ, Zhao JN, Rossi F, Antonescu CR, Balachandran VP, Cross JR, DeMatteo RP. Mitochondrial Inhibition Augments the Efficacy of Imatinib by Resetting the Metabolic Phenotype of Gastrointestinal Stromal Tumor. Clin Cancer Res. 2018 Feb 15;24(4):972-984. doi: 10.1158/1078-0432.CCR-17-2697. Epub 2017 Dec 15. PMID: 29246941; PMCID: PMC5815929.
5: Zhang X, Mofers A, Hydbring P, Olofsson MH, Guo J, Linder S, D'Arcy P. MYC is downregulated by a mitochondrial checkpoint mechanism. Oncotarget. 2017 Oct 6;8(52):90225-90237. doi: 10.18632/oncotarget.21653. PMID: 29163823; PMCID: PMC5685744.
6: Martin TD, Cook DR, Choi MY, Li MZ, Haigis KM, Elledge SJ. A Role for Mitochondrial Translation in Promotion of Viability in K-Ras Mutant Cells. Cell Rep. 2017 Jul 11;20(2):427-438. doi: 10.1016/j.celrep.2017.06.061. PMID: 28700943; PMCID: PMC5553568.
7: Fryknäs M, Zhang X, Bremberg U, Senkowski W, Olofsson MH, Brandt P, Persson I, D'Arcy P, Gullbo J, Nygren P, Schughart LK, Linder S, Larsson R. Iron chelators target both proliferating and quiescent cancer cells. Sci Rep. 2016 Dec 7;6:38343. doi: 10.1038/srep38343. PMID: 27924826; PMCID: PMC5141479.
8: Urra FA, Weiss-López B, Araya-Maturana R. Determinants of Anti-Cancer Effect of Mitochondrial Electron Transport Chain Inhibitors: Bioenergetic Profile and Metabolic Flexibility of Cancer Cells. Curr Pharm Des. 2016;22(39):5998-6008. doi: 10.2174/1381612822666160719122626. PMID: 27510477.
9: Wang L, Zhao S, Bao G, Zhang Y, Xi S, Zhou G, Zhai X, Gong P. Design, Synthesis, and Cytotoxicity of Novel 2,4,6-Trisubstituted 1,3,5- triazines Bearing Aryl Hydrazone Moiety as Potent Antitumor Agent. Med Chem. 2016;12(7):621-630. doi: 10.2174/1573406412666160106154551. PMID: 26732116.
10: Zhang X, Fryknäs M, Hernlund E, Fayad W, De Milito A, Olofsson MH, Gogvadze V, Dang L, Påhlman S, Schughart LA, Rickardson L, D'Arcy P, Gullbo J, Nygren P, Larsson R, Linder S. Induction of mitochondrial dysfunction as a strategy for targeting tumour cells in metabolically compromised microenvironments. Nat Commun. 2014;5:3295. doi: 10.1038/ncomms4295. PMID: 24548894; PMCID: PMC3929804.
Upon infusion, in normal cells and proliferating tumor cells where glucose is readily available, inhibition of OxPhos by VLX600 induces a hypoxia-inducible factor 1-alpha (HIF-1alpha)-dependent shift to, and an increase in glycolysis. Glycolysis alone does not produce enough energy to support the growth of tumor cells in this environment, and the induction of autophagy occurs. In the metabolically compromised tumor microenvironment, the availability of oxygen and glucose is limited due to poor vascularization and perfusion of tumor micro-areas. Tumor cells growing in this environment are thus unable to compensate for decreased mitochondrial function by increasing glycolysis. This leads to nutrient depletion, decreased energy production, induction of autophagy, tumor cell death and an inhibition of cell proliferation in quiescent tumor cells. Mitochondrial OxPhos, which is hyperactivated in cancer cells, plays a key role in the promotion of cancer cell proliferation.
